The AD tau core spontaneously self-assembles and recruits full-length tau to filaments

Yari Carlomagno; Sireesha Manne; Michael DeTure; Mercedes Prudencio; Yong Jie Zhang; Rana Hanna Al-Shaikh; Judith A. Dunmore; Lillian M. Daughrity; Yuping Song; Monica Castanedes-Casey; Laura J. Lewis-Tuffin; Katharine A. Nicholson; Zbigniew K. Wszolek; Dennis W. Dickson; Anthony W.P. Fitzpatrick; Leonard Petrucelli; Casey N. Cook

doi:10.1016/j.celrep.2021.108843

The AD tau core spontaneously self-assembles and recruits full-length tau to filaments

Yari Carlomagno, Sireesha Manne, Michael DeTure, Mercedes Prudencio, Yong Jie Zhang, Rana Hanna Al-Shaikh, Judith A. Dunmore, Lillian M. Daughrity, Yuping Song, Monica Castanedes-Casey, Laura J. Lewis-Tuffin, Katharine A. Nicholson, Zbigniew K. Wszolek, Dennis W. Dickson, Anthony W.P. Fitzpatrick, Leonard Petrucelli, Casey N. Cook

Research output: Contribution to journal › Article › peer-review

Abstract

Tau accumulation is a major pathological hallmark of Alzheimer's disease (AD) and other tauopathies, but the mechanism(s) of tau aggregation remains unclear. Taking advantage of the identification of tau filament cores by cryoelectron microscopy, we demonstrate that the AD tau core possesses the intrinsic ability to spontaneously aggregate in the absence of an inducer, with antibodies generated against AD tau core filaments detecting AD tau pathology. The AD tau core also drives aggregation of full-length wild-type tau, increases seeding potential, and templates abnormal forms of tau present in brain homogenates and antemortem cerebrospinal fluid (CSF) from patients with AD in an ultrasensitive real-time quaking-induced conversion (QuIC) assay. Finally, we show that the filament cores in corticobasal degeneration (CBD) and Pick's disease (PiD) similarly assemble into filaments under physiological conditions. These results document an approach to modeling tau aggregation and have significant implications for in vivo investigation of tau transmission and biomarker development.

Original language	English (US)
Article number	108843
Journal	Cell reports
Volume	34
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2021.108843
State	Published - Mar 16 2021

Keywords

Alzheimer's disease
Pick's disease
aggregation
biomarker
corticobasal degeneration
filament core
neurofibrillary tangles
real-time quaking-induced conversion
tau
tauopathy

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1016/j.celrep.2021.108843

Cite this

Carlomagno, Y., Manne, S., DeTure, M., Prudencio, M., Zhang, Y. J., Hanna Al-Shaikh, R., Dunmore, J. A., Daughrity, L. M., Song, Y., Castanedes-Casey, M., Lewis-Tuffin, L. J., Nicholson, K. A., Wszolek, Z. K., Dickson, D. W., Fitzpatrick, A. W. P., Petrucelli, L., & Cook, C. N. (2021). The AD tau core spontaneously self-assembles and recruits full-length tau to filaments. Cell reports, 34(11), [108843]. https://doi.org/10.1016/j.celrep.2021.108843

Carlomagno, Y, Manne, S, DeTure, M , Prudencio, M , Zhang, YJ, Hanna Al-Shaikh, R, Dunmore, JA, Daughrity, LM, Song, Y, Castanedes-Casey, M, Lewis-Tuffin, LJ, Nicholson, KA, Wszolek, ZK , Dickson, DW, Fitzpatrick, AWP, Petrucelli, L & Cook, CN 2021, 'The AD tau core spontaneously self-assembles and recruits full-length tau to filaments', Cell reports, vol. 34, no. 11, 108843. https://doi.org/10.1016/j.celrep.2021.108843

@article{337ca55293b84297a80b942949d286b3,

title = "The AD tau core spontaneously self-assembles and recruits full-length tau to filaments",

abstract = "Tau accumulation is a major pathological hallmark of Alzheimer's disease (AD) and other tauopathies, but the mechanism(s) of tau aggregation remains unclear. Taking advantage of the identification of tau filament cores by cryoelectron microscopy, we demonstrate that the AD tau core possesses the intrinsic ability to spontaneously aggregate in the absence of an inducer, with antibodies generated against AD tau core filaments detecting AD tau pathology. The AD tau core also drives aggregation of full-length wild-type tau, increases seeding potential, and templates abnormal forms of tau present in brain homogenates and antemortem cerebrospinal fluid (CSF) from patients with AD in an ultrasensitive real-time quaking-induced conversion (QuIC) assay. Finally, we show that the filament cores in corticobasal degeneration (CBD) and Pick's disease (PiD) similarly assemble into filaments under physiological conditions. These results document an approach to modeling tau aggregation and have significant implications for in vivo investigation of tau transmission and biomarker development.",

keywords = "Alzheimer's disease, Pick's disease, aggregation, biomarker, corticobasal degeneration, filament core, neurofibrillary tangles, real-time quaking-induced conversion, tau, tauopathy",

author = "Yari Carlomagno and Sireesha Manne and Michael DeTure and Mercedes Prudencio and Zhang, {Yong Jie} and {Hanna Al-Shaikh}, Rana and Dunmore, {Judith A.} and Daughrity, {Lillian M.} and Yuping Song and Monica Castanedes-Casey and Lewis-Tuffin, {Laura J.} and Nicholson, {Katharine A.} and Wszolek, {Zbigniew K.} and Dickson, {Dennis W.} and Fitzpatrick, {Anthony W.P.} and Leonard Petrucelli and Cook, {Casey N.}",

note = "Funding Information: We would like to thank the patients and their families for their participation in this work. Human postmortem brain samples and associated data were provided by the Mayo Clinic Brain Bank. We would also like to thank Katie Vicari for the artwork depicted in the graphical abstract. This work was supported by Mayo Clinic Foundation (L.P. and D.W.D.); The Liston Family Foundation (L.P.); Mayo Clinic Center for Regenerative Medicine (Z.K.W.); Mayo Clinic Neuroscience-Focused Research Team (Z.K.W.); National Institutes of Health/National Institute on Aging ( R01AG063780 [C.N.C.], ADRC 2 P50 AG016574-16 [L.P. and D.W.D.], and R01AG062171 [L.P.]); National Institutes of Health/National Institute of Neurological Disorders and Stroke ( U54NS100693 [L.P., D.W.D., and C.N.C.], R35NS097273 [L.P.], and U01NS110438 [A.W.P.F. and L.P.]); and Cure Alzheimer's Fund (L.P. and A.W.P.F.). In addition, this work was also supported by gifts from The Sol Goldman Charitable Trust (Z.K.W.), the Donald G. and Jodi P. Heeringa Family (Z.K.W.), the Haworth Family Professorship in Neurodegenerative Diseases fund (Z.K.W.), and The Albertson Parkinson{\textquoteright}s Research Foundation (Z.K.W.). Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = mar,

day = "16",

doi = "10.1016/j.celrep.2021.108843",

language = "English (US)",

volume = "34",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "11",

}

TY - JOUR

T1 - The AD tau core spontaneously self-assembles and recruits full-length tau to filaments

AU - Carlomagno, Yari

AU - Manne, Sireesha

AU - DeTure, Michael

AU - Prudencio, Mercedes

AU - Zhang, Yong Jie

AU - Hanna Al-Shaikh, Rana

AU - Dunmore, Judith A.

AU - Daughrity, Lillian M.

AU - Song, Yuping

AU - Castanedes-Casey, Monica

AU - Lewis-Tuffin, Laura J.

AU - Nicholson, Katharine A.

AU - Wszolek, Zbigniew K.

AU - Dickson, Dennis W.

AU - Fitzpatrick, Anthony W.P.

AU - Petrucelli, Leonard

AU - Cook, Casey N.

N1 - Funding Information: We would like to thank the patients and their families for their participation in this work. Human postmortem brain samples and associated data were provided by the Mayo Clinic Brain Bank. We would also like to thank Katie Vicari for the artwork depicted in the graphical abstract. This work was supported by Mayo Clinic Foundation (L.P. and D.W.D.); The Liston Family Foundation (L.P.); Mayo Clinic Center for Regenerative Medicine (Z.K.W.); Mayo Clinic Neuroscience-Focused Research Team (Z.K.W.); National Institutes of Health/National Institute on Aging ( R01AG063780 [C.N.C.], ADRC 2 P50 AG016574-16 [L.P. and D.W.D.], and R01AG062171 [L.P.]); National Institutes of Health/National Institute of Neurological Disorders and Stroke ( U54NS100693 [L.P., D.W.D., and C.N.C.], R35NS097273 [L.P.], and U01NS110438 [A.W.P.F. and L.P.]); and Cure Alzheimer's Fund (L.P. and A.W.P.F.). In addition, this work was also supported by gifts from The Sol Goldman Charitable Trust (Z.K.W.), the Donald G. and Jodi P. Heeringa Family (Z.K.W.), the Haworth Family Professorship in Neurodegenerative Diseases fund (Z.K.W.), and The Albertson Parkinson’s Research Foundation (Z.K.W.). Publisher Copyright: © 2021 The Authors

PY - 2021/3/16

Y1 - 2021/3/16

N2 - Tau accumulation is a major pathological hallmark of Alzheimer's disease (AD) and other tauopathies, but the mechanism(s) of tau aggregation remains unclear. Taking advantage of the identification of tau filament cores by cryoelectron microscopy, we demonstrate that the AD tau core possesses the intrinsic ability to spontaneously aggregate in the absence of an inducer, with antibodies generated against AD tau core filaments detecting AD tau pathology. The AD tau core also drives aggregation of full-length wild-type tau, increases seeding potential, and templates abnormal forms of tau present in brain homogenates and antemortem cerebrospinal fluid (CSF) from patients with AD in an ultrasensitive real-time quaking-induced conversion (QuIC) assay. Finally, we show that the filament cores in corticobasal degeneration (CBD) and Pick's disease (PiD) similarly assemble into filaments under physiological conditions. These results document an approach to modeling tau aggregation and have significant implications for in vivo investigation of tau transmission and biomarker development.

AB - Tau accumulation is a major pathological hallmark of Alzheimer's disease (AD) and other tauopathies, but the mechanism(s) of tau aggregation remains unclear. Taking advantage of the identification of tau filament cores by cryoelectron microscopy, we demonstrate that the AD tau core possesses the intrinsic ability to spontaneously aggregate in the absence of an inducer, with antibodies generated against AD tau core filaments detecting AD tau pathology. The AD tau core also drives aggregation of full-length wild-type tau, increases seeding potential, and templates abnormal forms of tau present in brain homogenates and antemortem cerebrospinal fluid (CSF) from patients with AD in an ultrasensitive real-time quaking-induced conversion (QuIC) assay. Finally, we show that the filament cores in corticobasal degeneration (CBD) and Pick's disease (PiD) similarly assemble into filaments under physiological conditions. These results document an approach to modeling tau aggregation and have significant implications for in vivo investigation of tau transmission and biomarker development.

KW - Alzheimer's disease

KW - Pick's disease

KW - aggregation

KW - biomarker

KW - corticobasal degeneration

KW - filament core

KW - neurofibrillary tangles

KW - real-time quaking-induced conversion

KW - tau

KW - tauopathy

UR - http://www.scopus.com/inward/record.url?scp=85102596049&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85102596049&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.108843

DO - 10.1016/j.celrep.2021.108843

M3 - Article

C2 - 33730588

AN - SCOPUS:85102596049

SN - 2211-1247

VL - 34

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 108843

ER -

The AD tau core spontaneously self-assembles and recruits full-length tau to filaments

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this